Fluid transfer systems, devices, and methods for biotreatment

Abstract

A device for collecting a fluid sample from a fluid-containing consumable in a biological treatment system, the consumable having a tube fluidly connected thereto, the device comprising: a fluid connection portion configured to connect with the tube of the fluid-containing consumable and to pump fluid or air through the device; and an air input portion configured to allow sterile air to be provided to the device; a sampling portion connected to the fluid connection portion wherein, during pumping into the device, the sampling portion is configured to receive a fluid sample from the consumable via the fluid connection portion; the first end of the bypass pipe is connected with the fluid connecting part, the second end of the bypass pipe is connected with the air input part, and the bypass pipe is configured to receive air provided by the air input part and guide the air out of the device through the fluid connecting part without passing through the sampling part, so that fluid in a pipe connected to the consumable is cleared; and means for restricting fluid flow through each of the sampling portion and the bypass pipe such that fluid pumped into the fluid connection portion only enters the sampling portion and air pumped out of the fluid connection portion only passes through the bypass pipe.

Description

Technical Field

[0001] The present invention relates to automated bioprocessing systems, for example, bioprocessing systems for performing cell therapy. Background Art

[0002] Increasingly, therapeutic drugs start with cells rather than small molecules. The methods for making these products are evolving rapidly to keep up with the constant stream of new treatments. In recent years, many new categories of cell therapy have become more widely used. One category is autologous cell therapy.

[0003] Autologous cell therapies are a class of therapeutics with significant clinical and commercial potential, with applications ranging from treating cancer to repairing genetic defects. These therapies involve removing cells from a patient, manipulating them over a period of days to weeks, and then reintroducing them into the patient to produce a therapeutic effect. The steps taken for autologous cell therapies are often complex; for example, a typical CAR-T process may involve a series of steps starting with cryopreserved leukocyte apheresis, followed by thawing, washing to remove DMSO, enrichment of T cells, activation, transduction, expansion, concentration, and finally formulation into IV bags, cryopreservation, with other intermediate washing steps.

[0004] To accomplish the above steps, bioprocessing systems have been developed. In such bioprocessing systems, for example, the entire cell therapy process may require a variety of different consumables (e.g., bags containing fluids) to provide culture media, reagents, and / or cell materials to a separate consumable called an "amplification chamber" (or "cell culture chamber"). Similarly, one or more consumables (e.g., output or waste bag consumables) can receive fluid samples from the amplification chamber. Therefore, the term "consumable" can be used to refer to the "disposable" elements or components of the system.

[0005] Some of the processes discussed above, such as activation, transduction, and expansion, can be performed in a cell culture chamber (or "bioreactor") where the cells can be cultured. In one or more of these processes, various functions need to be performed, such as the addition and removal of culture medium, harvesting, and sampling.

[0006] However, due to the need to maintain a closed system when handling cells, reagents and other fluids, traditional consumables (e.g., media bags) contain complex external flexible tubing networks for interfacing with the culture chamber. Such flexible tubing networks are difficult to handle, especially by automated devices, such as robotic devices.

[0007] An alternative approach is to connect each consumable to its own flexible tube and complete the connections between the consumables individually throughout the process. More specifically, the flexible tubes can be connected together using tube welding, the pump can deliver fluid through the connected tubes, and then the tubes can be disconnected again to facilitate further connections between other consumables.

[0008] However, there are many reasons why tube welding would seem incompatible with full (operator-independent) automation. For example, tube welding requires the handling of long flexible tubes, which are notoriously difficult to handle by automated handling devices such as robots. For example, flexible tubing is unlikely to remain in a well-defined, deterministic position when being moved by a robot, which makes joining, aligning, and orienting the tubes challenging.

[0009] When a sufficiently long flexible tube is constrained at one end and manipulated at the other, the path defined by the tube will have multiple non-unique solutions for what the path between the constrained end and the manipulated end will be, depending on the internal stresses in the tube. Such a system has many degrees of freedom. This application is ideal for humans but very challenging to automate and is therefore typically left to manual labor. Because the strength of the weld is so dependent on the precise positioning and compression of the tube, any error by the robot in joining the tubing may result in a failed weld. It is also challenging to avoid the tube becoming twisted and / or entangled with other tubes and other components of the bioprocessing system. In addition, the tube may apply unexpected tension to the robot or any connected consumables, reducing the likelihood of a successful weld or even potentially damaging the connection to the consumable.

[0010] Another problem that can arise when using multiple lengths of flexible tubing is that when fluid is pumped between a first consumable and a second consumable, a large amount of fluid may remain in the tube itself, even if there is enough fluid to reach the second consumable. This portion of fluid is called "dead volume" and can result in fluid waste in bioprocessing operations, especially when multiple long lengths of tubing are required to connect consumables. This is particularly problematic when only a small amount of sample needs to be removed from the consumable, which can happen frequently in bioprocessing operations.

[0011] Therefore, for at least the reasons stated above, it has heretofore been considered impractical to develop a bioprocessing system to utilize flexible pipes connected by automated pipe welding.It is an object of the present invention to address the above-mentioned problems. Summary of the invention

[0012] According to the first aspect described herein, there is provided a device for collecting a fluid sample from a fluid-containing consumable in a biological processing system, the consumable having a tube connected to its fluid, the device comprising: a fluid connection portion configured to be connected to the tube of the fluid-containing consumable and to pump fluid or air through the device; and an air input portion configured to allow sterile air to be provided to the device; a sampling portion connected to the fluid connection portion, wherein the sampling portion is configured to receive a fluid sample from the consumable via the fluid connection portion during pumping into the device; a bypass tube having a first end connected to the fluid connection portion and a second end connected to the air input portion, wherein the bypass tube is configured to receive air provided from the air input portion and guide the air out of the device via the fluid connection portion without passing through the sampling portion, thereby clearing the fluid in the tube connected to the consumable; and a device for limiting the flow of fluid through each of the sampling portion and the bypass tube, so that the fluid pumped into the fluid connection portion only enters the sampling portion, and the air pumped out of the fluid connection portion only passes through the bypass tube.

[0013] In this way, once the fluid is pumped into the device from the fluid-containing consumable (e.g., using a peristaltic pump connected to a flexible tube of the consumable), the fluid sample can be collected in the sampling portion. Subsequently, in order to prevent excess fluid from remaining in the tube connected to the consumable, the excess fluid can be "purged" by reversing the pumping direction to return the fluid to the consumable. Since the bypass allows the air-filled tube to replace the purged fluid, the fluid sample is retained in the device, and the excess fluid is removed. Therefore, the device can allow representative fluid samples to be collected from the consumable without wasting a large amount of fluid. Alternatively or additionally, the device can also be used to perform fluid removal at other nodes of the bioprocessing operation (e.g., nodes other than the sample collection in the device). In at least one embodiment, the tube connected to the fluid-containing consumable can be a flexible (non-rigid) tube; alternatively, in another embodiment, the tube can be set to a (rigid) fluid manifold containing the fluid consumable or formed as a part of a (rigid) fluid manifold containing the fluid consumable. Thus, the terms "tube" and "conduit" may refer to any type of fluid passage that functions as a "tube" or "conduit", whether rigid or flexible.

[0014] The device may further include: a sampling tube, a first end of which is connected to the fluid connection part, and a second end of which is connected to the air input part, wherein the sampling part is arranged between the first end and the second end of the sampling tube.

[0015] In this way, air expelled from the sampling portion when receiving a sample can be removed from the device via the air input portion; this allows the sampling portion to be made of a substantially rigid material. Alternatively, the sampling portion can be a flexible bag that can expand when receiving a fluid sample, thereby accommodating the increase in volume of the sampling portion without expelling air.

[0016] Preferably, the sampling portion is provided by a sample container disposed between the first end and the second end of the sampling tube. Alternatively, the sampling tube itself is of sufficient length to hold the fluid sample.

[0017] The sample container may have a conical shape. In this way, the fluid can enter the sample container from the narrow end of the cone and then fill up toward the wide end. This allows the volume of the fluid sample to be accurately determined in proportion, whether it is a small fluid sample or a large fluid sample.

[0018] The sampling portion may include an extraction port for removing a fluid sample from the sampling portion. The extraction port may be a needle-free sampling port, or a Luer lock cap port.

[0019] The means for limiting the flow of fluid through the device may include a first check valve to allow fluid to flow (only) from the fluid connection portion into the sampling portion. The (first) check valve limits the fluid sample from being discharged from the sampling portion, for example under the action of gravity. Furthermore, in the case where the sampling portion is provided by a sampling tube connected to the air input portion, the first check valve prevents air from clearing the fluid sample from the sampling portion, but forces air to flow from the air input portion through the bypass tube to the fluid connection portion.

[0020] Preferably, the check valve is located on the sampling tube between the sampling part and the air input part. In this way, the fluid sample can be collected in the sampling part without passing through the (first) check valve, which makes the valve act as an air valve operating in a dry state.

[0021] The means for restricting fluid flow through the device may comprise a second non-return valve to allow air to flow (only) from the air input portion through the bypass conduit to the fluid connection portion.

[0022] The second check valve restricts air from flowing from the fluid connection portion to the air input portion via the bypass pipe.

[0023] Preferably, one or both of the check valves are configured to inhibit fluid passage (eg, only allow air to pass). In this way, fluid cannot pass through the device to the air input portion, and the device can be operated in either direction within a bioprocessing system.

[0024] Alternatively, the means for restricting fluid flow through the device may include a clampable tubing portion on the sampling portion and the bypass tube; in this way, one or both clampable portions may be clamped closed to restrict fluid flow.

[0025] The fluid connection portion may comprise a length of (eg flexible) tubing, thereby enabling the device to be connected to a tube of the consumable by tube welding.

[0026] By using tube welding to connect the fluid connections to the consumables, a closed system is maintained throughout the sampling process, reducing the possibility of the surrounding environment contaminating the bioprocessing system. Since tube welding can be used for other connections in the bioprocessing system, no separate connection process is required for sampling.

[0027] The air input portion can be an air filter configured to provide sterile air from the surrounding environment. Alternatively, the air input portion can include a sterile air container. For example, the container can include a syringe or bag containing sterile air.

[0028] Preferably, the air input portion is a single air input portion connected to both the sampling portion and the bypass tube. Alternatively, the sampling portion and the bypass tube may be connected to separate air supplies, such as separate air filters or separate sterile air containers. Preferably, where the air input portion is a single air input portion, the air input portion is connected to both the sampling tube and the bypass tube via a single tube (e.g., via a Y-joint or splitter).

[0029] The device may also include an outer housing. In this manner, the device may be manipulated by a robotic device of a bioprocessing system. In addition, the device may be connected to other parts of a bioprocessing system (e.g., a bioprocessing apparatus) via the outer housing; the outer housing may have one or more engagement features to facilitate installation of the device in a bioprocessing system and / or manipulation of the device by a robotic device. The outer housing may hold components of the device (e.g., a fluid connection, an air input, and / or an extraction port) in predetermined positions to facilitate consistent engagement by a robotic device.

[0030] According to another aspect described herein, a sampling cartridge is provided, comprising a housing configured to hold one or more devices as described above and herein, in such a manner that a robotic device can engage the cartridge, move it within a bioprocessing system, and engage one of the devices held within the housing when performing a sampling operation.

[0031] According to another aspect described herein, a method for collecting a fluid sample using the device described above and herein is provided, comprising: connecting a fluid connection portion to a tube connected to a consumable; pumping fluid from the consumable into a sampling portion of the device via the fluid connection portion; and pumping the remaining fluid in the tube back to the consumable, thereby drawing air from the air input portion into the tube via a bypass tube.

[0032] According to another aspect of the present invention, a consumable for a bioprocessing system is provided, the consumable comprising: a container for a fluid; a tube having a first end connected to the container and extending to a second (e.g., free) end; and an air supply device, the fluid being connected to a position between the first end and the second end of the tube.

[0033] The air supply allows sterile air to be supplied to the tube. Advantageously, by providing the consumable with an air supply in fluid connection with the tube, air from the air supply can be used to purge fluid from the tube prior to any tube welding at (or near) the second (free) end of the tube. By removing the fluid from the second end of the tube, the tube welding is performed on a dry line, which is generally more reliable than a "wet" weld (where fluid is still present), thereby improving the reliability of the connection to the consumable.

[0034] The air supply device may include an air filter, and the air filter is configured to provide sterile air from the surrounding environment. The air supply device may include a sterile air container. The pipe connected to the container may be a first pipe, and the air supply device may be connected to the first pipe by a second pipe, for example, by welding. The (e.g., three-way) connection between the pipe and the air supply device may include one or more valves to control the flow of fluid or air into the pipe (e.g., from the second end of the container, the pipe and / or the air supply device). For example, one or more valves may be provided by a three-way valve or a stopcock. Alternatively, one or more valves may include two pinch valves (to allow control to flow through either or both of the pipe and the air supply device), or a pinch valve and a (straight-through) check valve. One or more valves may be integrated into the consumables, and preferably may be started externally, for example, by a robotic device and / or an external solenoid valve.

[0035] Alternatively, the (e.g., three-way) connection between the control (fluid or air) flow through the tube and the air supply can be performed externally. For example, during use, the consumable can be installed in a bioprocessing device, wherein the first tube and / or the second tube are retained in one or more valve seats. Thus, during use, the valve seat can be activated to restrict the flow of fluid or air through either or both of the first tube connected to the container and / or the second tube connected to the air supply.

[0036] Alternatively, the air supply device can be provided using the device described above and herein. The device can be connected to the tube via its fluid connection portion. Advantageously, using the device as an air supply device can both clear the fluid in the tube and also allow fluid sampling through the device.

[0037] According to another aspect described herein, there is provided a fluid connection system for a bioprocessing device, comprising: a consumable storage portion, the consumable storage portion having a first sub-portion and a second sub-portion, each sub-portion configured to store at least one fluid-containing consumable (having a flexible tube fluidly connected thereto); a cell storage portion, the cell storage portion configured to store a cell-containing consumable having at least a first flexible tube and a second flexible tube, each tube fluidly connected to the cell-containing consumable; a tube connection portion, the tube connection portion being arranged between the consumable storage portion and the cell storage portion. The tube connection portion comprises: a first portion configured to hold a first flexible tube containing a cell consumable and position it to connect to a flexible tube corresponding to the fluid-containing consumable stored in the first sub-portion of the consumable storage portion; a second portion configured to hold a second flexible tube containing a cell consumable and position it to connect to a flexible tube corresponding to the fluid-containing consumable stored in the second sub-portion of the consumable storage portion.

[0038] It should be understood that although the cell-containing consumable is described as having a first flexible tube and a second flexible tube, it may have more than two flexible tubes connected to the fluid, for example, three or more flexible tubes. Similarly, the fluid-containing consumable may also have more than one flexible tube connected to the fluid, for example, two or more flexible tubes. Since there may be multiple (e.g., four) fluid-containing consumables in the consumable storage portion, and there are multiple (e.g., two) tubes connected to the cell-containing consumable, the fluid connection system replaces the complex multi-to-multi-tube connection configuration with a two-to-multi-tube connection configuration, thereby simplifying the connection process.

[0039] In addition, by dividing the consumable storage portion into two sub-portions, wherein the corresponding portion of the tube connection portion is arranged to connect one of the flexible tubes containing the cell consumable to the tube in the corresponding sub-portion, a connection between the fluid-containing consumable and the cell-containing consumable can be formed without crossing the tube. This reduces the possibility of the tubes being entangled with each other and keeps the tubes in a roughly two-dimensional plane, thereby simplifying the manipulation of the tubes by the robotic device. The cell-containing consumable may be referred to as a "cell consumable" in this article. The cell-containing consumable may be a cell culture chamber.

[0040] Preferably, the cell-containing consumable is a bioreactor and the cell storage portion is a bioreactor platform arranged to receive the bioreactor thereon. The bioreactor platform may include a shaker for agitating the bioreactor to resuspend the cells. Alternatively, the bioreactor platform may be a static platform.

[0041] Preferably, the tube connection portion is further configured to arrange the first flexible tube containing the cell consumable and the second flexible tube to be connected to the air supply device. In this way, the air supply device can clear the fluid in the first flexible tube containing the cell consumable and the second flexible tube, thereby reducing the waste of residual fluid / cells in the tube (e.g., from sampling operations).

[0042] Preferably, the tube connection portion is further configured to arrange the first flexible tube and / or the second flexible tube containing the cell consumable to be connected to the sample collection device. The sample collection device may include at least one sample container, into which the fluid in the cell consumable can be pumped to collect a representative sample.

[0043] Preferably, the tube connection portion is configured to arrange the first flexible tube and / or the second flexible tube containing the cell consumable to a single device, the single device providing the air supply means and the sample collection means. Preferably, the single device is the device described above and herein.

[0044] The consumable storage portion may include a plurality of consumable holding positions, preferably arranged in a linear configuration. The consumable holding positions are preferably evenly spaced. Preferably, each consumable holding position is provided by a slot, each slot being configured to receive a fluid-containing consumable. Preferably, the fluid-containing consumable is contained in a box, each slot comprising one or more engagement features for releasably holding the box in the slot. Therefore, the fluid-containing consumable may be referred to as a "box consumable" in this article. Alternatively, the fluid-containing consumable may be suspended on a linear shelf, wherein the consumable holding position is defined by adjacent positions on the shelf.

[0045] Preferably, a plurality of consumable holding positions include an intermediate position, which is included in both the first subsection and the second subsection of the consumable storage portion. For example, in the case where there are a total of five positions for fluid-containing consumables in the consumable storage portion, the first subsection may include positions one to three, and the second subsection may include positions three to five. This arrangement can still prevent the tubes from crossing when a connection is made to the first flexible tube containing cell consumables or the second flexible tube containing cell consumables from the intermediate position. Alternatively, the subsections may be separate and non-overlapping, and the position of the fluid-containing consumable cannot be in the first subsection and the second subsection at the same time.

[0046] Preferably, the consumable storage portion may include a third sub-portion configured to receive at least one fluid-containing consumable (having a flexible tube fluidically connected thereto), wherein the third sub-portion includes a consumable holding position that is neither part of the first sub-portion nor part of the second sub-portion. In other words, the consumable holding position (e.g., a "buffer" position) of the third sub-portion is not used to hold consumables connected to cell-containing consumables. In this way, the buffer position can be used to exchange a fluid-containing consumable held in the first sub-portion with a fluid-containing consumable held in the second sub-portion; this allows any fluid-containing consumable to be connected to any flexible tube of the cell-containing consumable without crossing any tubes.

[0047] The tube connection portion includes: a first group of tube clamps, wherein each consumable holding position in the first sub-portion corresponds to at least one tube clamp in the first group of tube clamps; and a second group of tube clamps, wherein each flexible tube connected to the cell-containing consumable corresponds to at least one tube clamp in the second group of tube clamps. In this way, the flexible tube can be held by the tube clamp at a predetermined position of the tube connection portion. Therefore, the robotic device can consistently engage the tube based on the known position of the tube clamp in the tube connection portion. Preferably, the tube clamps hold the flexible tubes (in the first group and / or the second group) parallel and / or evenly spaced from each other.

[0048] Preferably, each position of the consumable storage portion corresponds to a pair of tube clamps (or more) in the first group of tube clamps, and / or each flexible tube connected to the cell-containing consumable corresponds to a pair of tube clamps in the second group of tube clamps. In this way, when a tube is held by a pair of tube clamps, the tube is held between the tube clamps along a predetermined axis. Since a section of the tube is held along a predetermined (straight) axis, the robotic device can engage the tube more consistently. For example, if the robotic device includes a linear peristaltic pump, the pump can engage the tube along a predetermined axis of the tube between the pair of tube clamps to pump fluid through the tube.

[0049] At least one tube clamp may include: a tube socket having a contoured shape designed to receive a tube at a predetermined position of the tube socket; a retaining element movable between an open position and a closed position relative to the tube socket, wherein the open position is for allowing the tube to be received by the tube socket and the closed position is for retaining the tube at the predetermined position of the tube socket; an actuator configured to move the retaining element between the open position and the closed position; wherein the actuator is controllable to move the retaining element between a plurality of intermediate positions, wherein at each intermediate position, the retaining element applies a different force to the tube against the tube socket to control fluid flow through the tube. The intermediate positions also allow tubes of different sizes to be properly retained and clamped closed in the tube clamp.

[0050] At least one of the tube clamps may include at least one sensor for detecting one or more of: the presence of a portion of a tube in the tube clamp and / or whether the portion of a tube held in the tube clamp contains a fluid.

[0051] According to another aspect described herein, a bioprocessing device is provided, comprising the fluid connection system described above and herein. The consumable storage part, the cell storage part and the tube connection part may be provided by the bioprocessing device.

[0052] The bioprocessing equipment may also include one or more of a loading system, a storage system, a cultivation system, and an unloading system.

[0053] According to another aspect described herein, a bioprocessing system is provided, comprising the fluid connection system described above and herein and / or the bioprocessing device described above and herein.

[0054] The bioprocessing system may also include a robotic device configured to manipulate fluid connections between one or more flexible tubes of the bioprocessing system. The robotic device may include a robotic arm with a robotic end effector. The robotic device may include: a tube welder for forming a sterile connection between tubes; a peristaltic pump for pumping fluid through the connecting tubes; and / or a tube sealer for disconnecting and sealing the tubes. The robotic device may be provided as a stand-alone device of the bioprocessing apparatus, for example, a mobile manipulation unit that can be moved relative to the bioprocessing apparatus. Alternatively, the robotic device may be provided as part of the bioprocessing apparatus.

[0055] The robotic device is configured to form a connection between the tubes of the tube connection portion. Preferably, the robotic device is configured to connect the first flexible tube containing the cell consumable (e.g., only) to the flexible tube containing the fluid consumable in the first part of the tube connection portion, and connect the second flexible tube containing the cell consumable (e.g., only) to the flexible tube containing the fluid consumable in the second part of the tube connection portion. The robotic device only forms a connection of the tube from the first sub-portion of the consumable storage portion in the first part of the tube connection portion. The robotic device (e.g., only) forms a connection of the tube from the second sub-portion of the consumable storage portion in the second part of the tube connection portion.

[0056] In this way, the robotic device is operated so that connections are made without crossing the tubes, thereby reducing the likelihood of tube entanglement. The robotic device can be configured to perform a specific bioprocessing workflow, which defines steps (e.g., connection, pumping, disconnection, and / or sealing steps) that the robotic device performs in a specific order.

[0057] According to another aspect described herein, a method for connecting a first flexible tube connected to a first consumable with a second flexible tube connected to a second consumable is provided, the method comprising: using a robotic device to: engage the first flexible tube held in a first tube clamp and pull the first flexible tube through the first tube clamp to arrange the first flexible tube adjacent to the second flexible tube held in the second tube clamp; engage the second flexible tube while keeping the first flexible tube engaged with the robotic device; and weld the first flexible tube to the second flexible tube to form a (first) connecting tube that connects the first consumable to the second consumable.

[0058] The robotic device may include a tube welder having a first pair of jaws and a second pair of jaws, such that a first flexible tube may be engaged by the first pair of jaws while a second flexible tube may be (simultaneously) engaged by the second pair of jaws (or vice versa). Once both tubes are engaged, the tube welder may grip the tubes using the pair of jaws, heat and cut the tubes along a cutting plane (e.g., using a heated blade to melt the tubes during the cutting process), align the first flexible tube with the second flexible tube, and press the melted ends of the tubes together to form a connected tube. Preferably, the tube welder is disposed on a robotic end effector of the robotic device.

[0059] The method may also include removing the second pipe from the second pipe clamp before welding, and returning the connecting pipe to the second pipe clamp after welding. Advantageously, this provides more maneuvering space for the robot device when welding the first flexible pipe to the second flexible pipe.

[0060] The method may also include: sealing the connecting tube between the first tube clamp and the second tube clamp to divide it into a first flexible tube held in the first tube clamp and a second flexible tube held in the second tube clamp; engaging a third flexible tube held in the third tube clamp, the third flexible tube being connected to a third consumable, and pulling the third flexible tube through the third tube clamp to arrange the third flexible tube adjacent to the first flexible tube or the second flexible tube; engaging the first flexible tube or the second flexible tube while keeping the third flexible tube engaged with the robotic device; welding the third flexible tube to the first flexible tube or the second flexible tube to form a second connecting tube connecting the first consumable or the second consumable to the third consumable.

[0061] In this way, subsequent connections between flexible tubes can be made, wherein the tubes are always held by tube clamps or robotic devices; therefore, the position and movement of all tubes are known at all stages when making connections between consumables, reducing the possibility of incorrect connections.

[0062] According to another aspect described herein, there is provided a pipe clamp for holding a portion of a flexible pipe, comprising: a pipe seat configured to receive the pipe in a predetermined position; a retaining element movable relative to the pipe seat between an open position and a closed position, the open position being used to allow the pipe to be received by the pipe seat in the predetermined position, and the closed position being used to retain the pipe in the pipe seat; an actuator configured to move the retaining element between the open position and the closed position; wherein the actuator is further configured to move the retaining element beyond the closed position so that the pipe is at least partially clamped against the pipe seat, thereby controlling the flow of fluid through the pipe. The pipe clamp can be disposed in a fluid connection system as described above. The pipe seat can be configured to receive the pipe from a robotic device.

[0063] Thus, the actuator is controllable to move the retaining element between a plurality of intermediate positions, in each of which the retaining element applies a different force to the tube against the tube seat to control fluid flow through the tube and / or to allow tubes of different diameters to be used with the tube clamp. Advantageously, the tube clamp can clamp the tube closed (e.g., block the tube) to prevent fluid flow therethrough, can (tightly) hold the tube to restrict fluid flow therethrough, can (gently) hold the tube without significantly restricting fluid flow therethrough, and / or can completely release the tube from the tube clamp. The tube clamp can gently hold the tube, applying sufficient force to prevent longitudinal movement of the tube through the tube clamp; the tube clamp can also gently hold the tube to allow longitudinal movement through the tube clamp.

[0064] The following preferred features may be provided with the fluid connection system as described above and herein and / or the pipe clamp as described above and herein.

[0065] Preferably, the actuator is controllable to provide a continuous range of intermediate positions of the retaining element.Alternatively, the actuator may be controllable to apply a continuous range of forces to the tube against the tube seat.

[0066] The profile of the tube seat may be semicircular or generally C-shaped, rectangular, or may have a generally V-shaped notch or groove so that when force is applied to the tube against the tube seat, the tube is urged to a predetermined position, thereby facilitating consistent engagement of the tube in the tube clamp by an external robotic device.

[0067] The retaining element may include a retaining arm configured to seal the tube within the tube socket when the retaining element is in the closed position. The retaining arm may be a hook-shaped element, a rod element, or any other suitable shape for retaining the tube against the tube socket. One or more additional retaining arms may be used, for example, two rod elements on two separate pivots.

[0068] The pipe seat can include a first portion and a second portion spaced apart by a gap in a direction parallel to the pipe axis, wherein the retaining arm is arranged in the gap to contact the pipe. In this way, the retaining arm applies a symmetrical force to the pipe so that it will not bend during the engagement process.

[0069] Preferably, the actuator is configured to rotate the retaining element during movement from the open position to the closed position. In other words, the retaining element may be connected to a pivot about which the retaining element rotates. In this way, when the retaining element is in the open position, the tube seat may be fully exposed, thereby allowing the tube to be received in the tube seat without obstruction.

[0070] The tube clamp may also include a cam element rotationally coupled to the actuator, wherein rotation of the cam element both rotates the retaining element and laterally moves the retaining element during movement from the open position to the closed position. Thus, during initial movement of the retaining element from the open position to the closed position, the retaining element may be rotated so that the retaining arm is located in front of the tube seat. Subsequently, during subsequent movement of the retaining element, the cam element causes the retaining arm to move laterally toward the tube in a generally linear direction; this reduces shear forces applied to the tube (particularly when the tube is clamped in the closed position), thereby reducing the risk of tube breakage.

[0071] Preferably, the retaining element is biased by a spring to counteract the force applied by the actuator, thereby returning the retaining element to the open position when the actuator is disconnected. Like this, there is no need to control the actuator to actively rotate the retaining element toward the open position.

[0072] Preferably, the tube clamp is configured to enable the tube to be moved longitudinally therethrough. As used herein, the longitudinal movement of the tube preferably refers to the movement of the tube along the axis of the tube. By enabling the tube to move longitudinally, even if other parts of the tube are moving (e.g., to connect to other tubes), the position of at least part of the tube is still known. In this way, each tube can always be positioned using at least one tube clamp in the tube connection portion. The tube clamp may include a roller to enable the retained tube to move longitudinally. Preferably, the retaining element is movable to a position in which the tube is retained in the tube clamp but is not clamped or clamped by the retaining element. In this way, the tube does not necessarily have to contact the tube clamp in the closed position, so that the tube can be easily pulled longitudinally through the tube clamp while still maintaining the tube in a predetermined position in the bioprocessing system (so that the robotic device can engage). The tube contact surface of the retaining element and / or the tube holder may include a low friction surface so as not to significantly inhibit the longitudinal movement of the tube through the tube clamp.

[0073] The tube clamp may further comprise at least one sensor for detecting one or more of: the presence of a portion of the tube in the tube clamp and / or whether the portion of the tube held in the tube clamp contains a fluid.

[0074] The at least one sensor may comprise a bubble sensor. The sensor may comprise a capacitive sensor and / or an ultrasonic sensor. The sensor may comprise a force sensor for measuring the force or torque applied by the retaining arm to the tube. Preferably, a plurality of sensors are provided.

[0075] The pipe clamp may further comprise a pipe guide arranged to support the pipe along the (longitudinal) axis of the pipe at a predetermined position offset from the pipe seat.

[0076] In this way, the position of the tube is not only precisely known at the tube socket, but also over the extended length between the tube socket and the tube guide. This can enable an external robotic device to engage the tube more consistently. The tube guide may include tube fins arranged to extend along the (longitudinal) axis of the tube. This enables the robotic device to easily engage the tube because the fins support the tube and are thin enough not to block the closure of the jaws of the robotic device when the jaws engage the tube. The tube guide may include a second tube socket offset from the (e.g., first) tube socket along the longitudinal axis. In this way, the position of the tube is known both in the first tube socket and the second tube socket, as well as the axis extending therebetween, thereby enabling the tube to be engaged by the robotic device without being blocked by either tube socket.

[0077] Those skilled in the art will appreciate that any device feature described herein can be provided as a method feature, and vice versa. It will also be appreciated that the specific combination of various features in any aspect described and defined herein can be implemented and / or provided and / or used independently.

[0078] Furthermore, it should be understood that the invention described herein is exemplary only and modifications of detail may be made within the scope of the invention. Furthermore, as used herein, "means plus function" features may be expressed alternatively with respect to their corresponding structures. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] One or more embodiments will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0080] Figure 1 An example of a bioprocessing apparatus that may form part of a bioprocessing system is shown;

[0081] Figure 2A A cartridge containing cartridge consumables with tubes connected thereto is shown; Figure 2B A cell culture chamber with a plurality of tubes connected thereto is shown;

[0082] Figure 3 A first example of a fluid connection system for connecting a plurality of cartridge consumables to a cell culture chamber is shown;

[0083] Figure 4A A preferred example of a fluid connection system is shown;

[0084] Figure 4B Shows Figure 4A A pipe connection part of a fluid connection system;

[0085] FIG. 5A to FIG. 5D Shows the use of Figure 4B Method steps for connecting the fluid connection part of the pipe;

[0086] FIG. 6A to FIG. 6D An alternative fluid connection system is shown;

[0087] 7A to 7C An example of a sampling device that is also capable of removing fluid from a tube in a bioprocessing system is shown;

[0088] Fig. 8A and Figure 8B Shows the available Figure 4A Fluid connection systems and Figure 4B Examples of pipe clamps for pipe connection portions of the present invention; and

[0089] FIG. 9A to FIG. 9G Alternative methods by which the sample may be extracted are shown. DETAILED DESCRIPTION

[0090] Overview

[0091] Figure 1 A bioprocessing apparatus 1 is shown. The bioprocessing apparatus 1 may be part of a wider bioprocessing system, for example, a processing station of a bioprocessing system. The bioprocessing apparatus 1 may include a plurality of subsystems, such as a loading system, a storage system 20, a fluid connection system 30, an incubator system 40, and an unloading system. Figure 1 In the example shown, the loading system and the unloading system are omitted. Figure 1 Each system is shown at a specific location on the device 1 , but it should be understood that these locations are examples only and the systems may be located elsewhere.

[0092] The bioprocessing apparatus 1 is operable to receive a plurality of consumables and manipulate the consumables to perform a bioprocessing operation. For example, the bioprocessing operation may include steps such as fluid transfer between consumables, culturing of consumables, and sampling from consumables.

[0093] Each consumable has at least one flexible tube connected to its fluid; as will be described in detail later, fluid transfer between consumables is achieved by connecting the consumables together via their respective tubes and then by pumping fluid between them. More specifically, the corresponding tubes are welded together by a tube welder, the fluid is pumped using a peristaltic pump, and then the tubes are disconnected by a tube sealer. When the tubes are not connected together, the free end of each tube remains sealed so that the contents of each tube and the consumable are not exposed to the environment; this provides a "closed system" that prevents contamination of the contents of the container or the environment.

[0094] The input to the bioprocessing device 1 can be consumables containing reagents, culture media, cytokines and patient samples (such as cells), as well as empty consumables for collecting test samples. After the bioprocessing operation, the output of the bioprocessing device 1 can be, for example, consumables containing cell culture media, waste consumables or empty consumables.

[0095] The specific steps of the bioprocessing operation can be defined by a "bioprocessing workflow". All bioprocessing operation steps are preferably automated, and the manipulation of consumables (including fluid connection and transfer) is performed by the robotic device 5, preferably without any operator intervention. The robotic device 5 may have at least one robotic arm, wherein at least one end effector has the following components: a tube welder for forming a sterile connection between tubes, a peristaltic pump for pumping fluids through the connecting tubes, and / or a tube sealer for disconnecting and sealing tubes. These components can be arranged on the same end effector, or on different end effectors or different robotic devices.

[0096] The tube welder may have a first pair of jaws for gripping a first tube and a second pair of jaws for gripping a second tube. The peristaltic pump is preferably a linear peristaltic pump having a plurality of independent pressing elements that compress the retained tubes to achieve a peristaltic pumping action to pump fluid through the tubes. The tube sealer may include a radio frequency sealer or a heat sealer; alternatively, sealing may be performed by the tube welder.

[0097] like Figure 1 As shown, each part is accessible from the front surface 1a of the bioprocessing device 1. This enables the robotic device 5 to manipulate the consumables; for example, Figure 1 As shown, the robotic device 5 may be separate from the apparatus 1, for example a mobile manipulation unit that can move freely on the factory floor where the bioprocessing apparatus 1 is located. Alternatively, the robotic device 5 may be part of the bioprocessing apparatus 1, for example mounted on rails laid adjacent to the front surface 1a.

[0098] The term "consumable" is used to refer to components that directly contain and / or contact biological materials and therefore cannot be reused. More specifically, the consumable can be a container such as a bag or a jar. To facilitate handling and manipulation of the consumable, the consumable may be located in a cartridge 100, which will be described in conjunction with the following. Figure 2A and Figure 2B Give a description.

[0099] Figure 2AAn example of a cassette 100 for holding consumables 150 is shown. The consumables 150 held in the cassette 100 may be referred to as "cassette consumables" 150. The cassette 100 includes a first portion 120 for holding the cassette consumables 150, and a second portion 130 for at least partially holding a flexible tube 155 along a predetermined path. More specifically, the first portion 120 is provided by a housing 120, in which the cassette consumables 150 (in the form of a bag 150) are located. The second portion 130 may include one or more tube clamps 131 for holding the free end 155a of the tube 155 in a fixed position relative to the cassette 100 (and therefore relative to the slot), which enables the robotic device 5 to engage the tube 155 in a consistent position. For example, the tube 155 may be directly engaged in a position between two tube clamps 131. Alternatively, the cassette 100 may have only a single passive clamp 131. Preferably, the cartridge 100 is configured to be able to release and retract the tube 155 connected to the consumable 150; in this way, the cartridge 100 can accommodate changes in the length of the tube 155, 255 resulting from repeated connections.

[0100] Figure 2B An example of a cell consumable 250 (e.g., a cell culture chamber 250) is shown. The cell consumable 250 may be referred to as a "bioreactor" 250. The cell consumable may be a gas-permeable cell culture container. In this example, the cell consumable 250 is generally in the shape of a conical flask with an opening at the top, but this shape is only an example. The cell consumable 250 may be any jar, bottle, or container containing cells. A removable lid 254 (e.g., screwed) is mounted on the opening of the cell consumable 250. A plurality of tubes 255 extend through the lid 254 to pump fluids into and / or out of the cell consumable 250. For example, a first tube 255-1 may extend to the top of the cell consumable 250, and a second tube 255-2 may be retained at the bottom of the cell consumable 250; this allows fluids to be easily added from the top of the cell consumable 250 and removed from the bottom of the cell consumable 250. Optionally, other tubes may also be present, for example, a third tube 255-3. It should be understood that the configuration of tubes 255 may be different, and there may be more or fewer tubes 255 .

[0101] The tubes 255 extend from the cell consumable so that the robotic device 5 can contact these tubes 255. In this way, fluid can be added and / or removed from the cell consumable 250 via the tubes 255. The free ends 255a of the tubes are arranged to have a fixed position relative to the cell consumable 250, for example, by using one or more passive clamps (on the cell consumable 250 or on the fluid connection system 30); in this way, when the bioreactor 250 is installed in the bioprocessing system 1, the robotic device 5 can engage the tubes 255 in a consistent position. Although Figure 2B The bioreactor 250 is shown within an external incubator with a base and lid, but it should be understood that these components are not required.

[0102] As will be described later in conjunction with the fluid connection system 30, during bioprocessing operations, the flexible tube 155 corresponding to the box consumable 150 (referred to as the "box consumable tube 155") can be welded to the flexible tube 255 corresponding to the cell consumable 250 (referred to as the "cell consumable tube 255" or "bioreactor tube").

[0103] Although Figure 1 1 , but the (optional) loading system is now described. The loading system includes a plurality of loading slots. Each loading slot is configured to receive a box 100 that holds a box consumable 150, for example, a box consumable 150 containing a patient sample or a reagent. The housing 120 of the box 100 may have a standardized shape and / or one or more engaging components to consistently insert the box 100 into one of the loading slots. The box 100 may be loaded manually by a human operator, or loaded by an automated robotic device 5. The loading system also includes at least one bioreactor loading platform, wherein the cell consumable 250 can be initially loaded into the device 1. As previously described, the cell consumable 250 has a plurality of flexible tubes 255 to facilitate transferring fluid to or from the cell consumable 250.

[0104] The apparatus 1 includes a storage system 20. The storage system 20 includes a plurality of storage slots 22. Once loaded into the loading slot, the robotic device 5 can transfer the box 100 to the storage slot 22. Alternatively, the box 100 can be loaded directly into the storage slot 22 (i.e., no loading system is required). In this example, the storage slots 22 include a first set of storage slots 22a for room temperature storage, and a second set of storage slots 22b located in the freezer 23. In this way, many different types of box consumables 150 can be stored in a standardized box 100 within the bioprocessing apparatus 1, for example, box consumables 150 containing different reagents, culture media, or patient samples (such as cells); when needed, any box 100 can be removed from one of the storage slots 22 and moved to the fluid connection system 30 for fluid transfer. The storage system 20 may also have other parts, such as a culture medium storage section 26 for large culture medium bags; this allows culture medium to be loaded into the apparatus 1 in batches and subsequently transferred to the box 100 (rather than requiring a constant supply of smaller bags of culture medium in the box 100).

[0105] The fluid connection system 30 will now be described. During a bioprocessing operation, it may be necessary to transfer fluids between consumables, for example, from one or more box consumables 150 to a cell consumable 250, or vice versa. The fluid connection system 30 includes a consumable storage portion 31, which includes a plurality of transfer slots 32; for transfer operations, the robotic device 5 can move the box 100 from the storage slot 22 of the storage system 20 to the transfer slot 32 of the fluid connection system 30. The fluid connection system 30 also includes a cell consumable storage portion 34. The cell consumable storage portion 34 may include a bioreactor platform 35. For transfer operations, the bioreactor 250 can be moved onto the bioreactor platform 35, for example, from a bioreactor loading platform of a loading system.

[0106] Once the cartridge 100 is properly loaded into the fluid connection system 30, the tube 155 corresponding to each cartridge consumable 150 is located at a predetermined position relative to each transfer slot 32. Similarly, when the cell consumable 250 is properly loaded into the fluid connection system 30, the tube 255 connected to the cell consumable 250 is located at a predetermined position relative to the bioreactor platform 35. In this way, the robotic device 5 can reliably engage any tube 155, 255 connected to any consumable 150, 250 to form a connection between them. This will be described later in conjunction with Figure 3 Additional features of the fluid connection system 30 are discussed through FIG. 6 .

[0107] The incubator system 40 will now be described in more detail. Once the various reagents are mixed in the cell consumables 250 (e.g., after fluid transfer occurs in the fluid connection system 30), the cell consumables 250 can be moved to the incubator system 40 for cell amplification. Since the bioprocessing device 1 can perform multiple bioprocessing operations in parallel (i.e., for different patient samples), the incubator system 40 preferably includes a plurality of culture platforms 45, each of which is arranged to support corresponding cell consumables 250. The incubator system 40 encloses the cell consumables 250 in the culture chamber 43 to keep the cell consumables 250 at a temperature higher than room temperature, for example, about 37 degrees. The incubator system 40 can also be configured to agitate the contents of the cell consumables 250, for example, shaking or tilting the cell consumables 250. In particular, each culture platform 45 can be independently operated to agitate the cell consumables 250 placed thereon.

[0108] At various points in the bioprocessing workflow, the cell consumable 250 can be transferred from the incubator system 40 back to the fluid connection system 30. For example, a sample can be extracted from the cell consumable 250 to monitor cell growth.

[0109] Although Figure 11, the (optional) unloading system will now be described in more detail. The unloading system includes a plurality of unloading slots, which are similar to the loading slots, storage slots 22 and transfer slots 32 described previously. The unloading slots receive used boxes 100, for example, boxes 100 containing waste culture media, test samples, enriched cell cultures or empty boxes of box consumables 150. In this way, the used boxes 100 can be easily removed from the device 1 via the unloading system. Alternatively, the box 100 can be removed directly from the storage system 20 or the fluid connection system 30.

[0110] The unloading system also includes at least one bioreactor unloading platform, which can be similar to the bioreactor loading platform of the loading system. In this way, the used cell consumables 250 can be easily removed from the device 1 via the unloading system 50. Alternatively, the cell consumables 250 can be directly removed from the storage system 20 or the fluid connection system 30.

[0111] The bioprocessing apparatus 1 includes a user interface 60. In this example, the user interface 60 is a tablet computer connected to the bioprocessing apparatus 1, but it should be understood that the user interface 60 can also be set elsewhere, including remotely connected to the apparatus 1. The user interface 60 can be used by a human operator when loading a cartridge 100 into a loading system; for example, an operator can identify the contents of a cartridge 100 loaded into a loading slot. By storing this information in the apparatus 1, the location of all cartridges 100 as they move on the apparatus 1 (e.g., between slots 22, 32) can be tracked. The user interface 60 can allow a user to input a specific bioprocessing workflow to be followed, or instruct the apparatus 1 to perform a sampling operation.

[0112] Fluid connection system

[0113] The fluid connection system 30 will now be described in more detail. As described above, the fluid connection system 30 enables a connection to be formed between the tube 155 corresponding to the cartridge consumable 150 and the tube 255 corresponding to the cell consumable 250. Typically, there are four cartridges 100-1, 100-2, 100-3, 100-4 in the transfer tank 32, each cartridge holding a corresponding cartridge consumable 150-1, 150-2, 150-3, 150-4 connected to a corresponding tube 155-1, 155-2, 155-3, 155-4. The cell consumable 250 has at least two tubes 255-1, 255-2.

[0114] Ideally, a fluid connection system should be able to do the following:

[0115] First, the fluid connection system should be able to connect any tube 155 corresponding to any box consumable 150 to any tube 255 corresponding to the cell consumable 250.

[0116] Second, the fluid connection system should measure the volume of fluid transferred between each consumable 150, 250 throughout the bioprocessing workflow.

[0117] Third, because the tube 155 generally extends downward from the box 100, the fluid connection system should be able to prevent fluid from being discharged from the box consumable 150 under the action of gravity.

[0118] Fourth, the fluid connection system should be able to transfer samples from the cell consumable 250 to the sample container. This allows the progress of cell expansion in the cell consumable 250 to be monitored by taking representative samples throughout the bioprocessing method.

[0119] Fifth, due to the length of the pipeline extending between consumables 150 and 250, the fluid connection system should be able to remove any remaining fluid in tubes 155 and 255 after the transfer operation. For example, when the fluid is pumped from the box consumable 150 to the cell consumable 250 through the connecting tube, even if enough fluid has been transferred to the cell consumable 250, the extra fluid will remain in the connecting tube. If the fluid is not removed, but stays in the tube for a long time, the fluid may fail and contaminate other fluids in the closed system. In addition, the removed fluid is preferably returned to its original consumable, rather than being pumped into a waste container. When sampling in a sample container, the tube also needs to be cleared in a similar manner.

[0120] In practice, a fluid connection system that can perform all of the above functions is difficult to achieve.

[0121] Figure 3 A schematic diagram of a fluid connection system 30' is shown. As shown, the cell consumable 250 is connected to a first tube 255-1 and a second tube 255-2. In addition, a sampling unit 90 is provided, including a plurality of sample containers 95. In order to allow the tubes 255-1, 255-2 to be connected to both the cartridge consumable 150 and the sampling unit 90, the fluid connection system 30' requires the tubes 155, 255 to cross each other at multiple points. In practice, Figure 3 The fluid connection system 30' in requires a many-to-many connection configuration, which requires the tubes to cross at least one location.

[0122] However, in the case of automated bioprocessing workflows, crossing of tubes is problematic. First, the same pair of tubes may cross repeatedly when multiple connections and disconnections are made, resulting in tube entanglement. Second, crossing of tubes requires the tubes to move out of a substantially two-dimensional plane, which makes it difficult for a robotic device to reliably engage the tubes (in a consistent position). Third, only the first cell consumable tube 255-1 can be connected to the sampling unit 90, so sampling from the second cell consumable tube 255-2 is not possible.

[0123] In order to solve the above problems, Figure 4AA preferred embodiment of a fluid connection system 30 is shown. The system 30 includes a consumable storage portion 31 having a first sub-portion 31a and a second sub-portion 31b. Each sub-portion 31a, 31b is configured to store at least one fluid-containing consumable 150, and the fluid-containing consumable 150 has a flexible tube 155 connected to its fluid. More specifically, as described above, the consumable storage portion 31 has a plurality of slots 32, each slot 32 being configured to receive a box 100, in which the box 100 holds the box consumable 150. The slots 32 are preferably arranged in a linear configuration, and the slots 32 are evenly spaced. The slots 32 are divided into a first group of slots 32a and a second group of slots 32b, corresponding to the corresponding sub-portions 31a, 31b of the storage portion 31, respectively.

[0124] The fluid connection system 30 also includes a cell storage portion 34 configured to store a cell consumable 250 (eg, a cell culture chamber 250) having at least a first flexible tube 255a, 255b fluidly connected thereto.

[0125] The fluid connection system 30 also includes a tube connection portion 300 arranged between the consumable storage portion 31 and the cell storage portion 34. The tube connection portion 300 includes a first portion 300a and a second portion 300b, rather than allowing connection between any cartridge consumable 150 and any one of the tubes 255-1, 255-3 connected to the cell consumable 250. The first portion 300a is configured to hold a first flexible tube 255-1 of a cell consumable 250 and is positioned to connect to the flexible tubes 155-1, 155-2 corresponding to the cartridge consumable 150 stored in the first sub-portion 31a of the consumable storage portion 31. The second portion 300b is configured to hold a second flexible tube 255-2 of a cell consumable 250 and is positioned to connect to the flexible tubes 155-3, 155-4 corresponding to the cartridge consumable 150 stored in the second sub-portion 31b of the consumable storage portion 31.

[0126] Advantageously, by dividing the tube connection portion 300 into a first portion 300a and a second portion 300b, each portion being arranged to connect a tube in one of the sub-portions 31a, 31b of the consumable storage portion to one of the tubes 255-1, 255-2 of the cell consumable, a connection between the consumables 150, 250 can be formed without crossing the tubes 155, 255. This reduces the likelihood that the tubes 155, 255 will become entangled with one another and keeps the tubes 155, 255 in a substantially two-dimensional plane, thereby simplifying the manipulation of the tubes 155, 255 by the robotic device 5. Although Figure 4A31a and 31b. The consumable storage portion 31 may have a slot 32 at an intermediate position in both the first sub-portion 31a and the second sub-portion 31b. The consumable storage portion 31 may have a third sub-portion 31c, preferably provided by a single slot 32. In this way, when the tube 155-1, 155-2 of one of the cartridge consumables 150-1, 150-2 in the first sub-portion 31a needs to be connected to the second cell consumable tube 255-2 (or the tube 155-3, 155-4 of one of the cartridge consumables 150-3, 150-4 in the second sub-portion 31b needs to be connected to the first cell consumable tube 255-1), the slot 32 in the third sub-portion 31c can be used to exchange two cartridge consumables 150 between the first sub-portion 31a and the second sub-portion 31b. In other words, the third sub-portion 31c provides a buffer position for one of the cartridge consumables 150 so that only one cartridge consumable 150 needs to be engaged at a time for exchange. By allowing cartridge consumables 150 to be swapped between the first subsection 31a and the second subsection 31b, any cartridge consumable 150 can be connected to either cell consumable tube 255-1, 255-2 without crossing the tubes.

[0127] The fluid connection system 30 also includes a sampling device 400 that allows sampling from the cell consumable 250. 7A to 7C A specific example of the sampling device 400 is described. In short, the sampling device 400 allows sampling from the cell consumable 250 and includes an air input portion 420 that allows any remaining fluid in the tubes 255-1, 255-2 to be returned to the cell consumable 250 after the sampling operation.

[0128] Figure 4B The tube connection portion 300 is shown in more detail. In this example, the tube connection portion 300 is a tube connection panel 300 located between the consumable storage portion 31 (holding the cartridge consumables 150) and the cell storage portion 34 (holding the cell consumables 250) in the fluid connection system 30. During use, a plurality of tubes 155-1, 155-2, 155-3, 155-4, 155-5 may extend through the top edge 300a of the tube connection panel 300, each tube 155 corresponding to the cartridge consumables 150 in one of the slots 32 of the consumable storage portion 31. Similarly, a plurality of tubes 255-1, 255-2, 255-3 may extend through the bottom edge 300b of the tube connection panel 300, each tube 255 connected to the cell consumables 250 in the cell storage portion 34.

[0129] The pipe connection part 300 includes a plurality of pipe clamps 500 (only part of which is marked). Fig. 8A and Figure 8BA specific example of the tube clamp 500 is described. The tube clamp 500 includes a first group of tube clamps 500a, which are located near the top edge 300a of the tube connection panel 300; the first group of tube clamps can be referred to as "box consumable tube clamps 500a". In this way, each tube 155 corresponding to one of the box consumables 150 can be held in a predetermined position in the tube connection portion 300 by at least one box consumable tube clamp 500a. More specifically, the first box consumable tube 155-1 is held by at least one first box consumable tube clamp 500a-1. Preferably, the first box consumable tube 155-1 is held by a first pair of box consumable tube clamps 500a-1, 500a-1' (e.g., an "upper" box consumable tube clamp 500a-1 and a "lower" box consumable tube clamp 500a-1'). Likewise, each of the second to fifth cartridge consumable tubes 155 is held by at least one cartridge consumable tube clamp, preferably a pair of cartridge consumable tube clamps, although not all of the tube clamps are labeled for clarity. By using a pair of tube clamps 500a-1, 500a-1', the tube 155-1 is held between the pair of tube clamps along a predetermined axis. This enables the robotic device 5 to more consistently engage the tube 155-1, since the position of the tube 155-1 is known not only at a single point, but also along a continuous length of the tube 155-1.

[0130] The tube clamp 500 includes a second group of tube clamps 500b, which are located near the bottom edge 300b of the tube connection panel 300; the second group of tube clamps can be referred to as "cell consumable tube clamps 500b". In this way, each tube 255 connected to the cell consumable 250 can be held in a predetermined position in the tube connection portion 300 by at least one cell consumable tube clamp 500b. More specifically, the first cell consumable tube 255-1 is held by at least one first cell consumable tube clamp 500b-1. Preferably, the first box consumable tube 255-1 is held by a first pair of tube clamps 500b-1, 500b-1' (for example, an "upper" cell consumable tube clamp 500b-1 and a "lower" cell consumable tube clamp 500b-1'). Likewise, each of the second (and third) cell consumable tubes 255 is held by at least one cell consumable tube clamp, preferably a pair of cell consumable tube clamps, although not all of the tube clamps are labeled for clarity. The distance between the tube clamp pairs in the second set of tube clamps 500b can be greater than the distance between the cell consumable tube clamp pairs; this can provide additional space for the linear peristaltic pump to be arranged on the tube axis between the cell consumable tube clamp pairs.

[0131] Although Figure 4B Not shown, the sampling device 400 can be mounted in the center of the tube connection portion 300 so that any cell consumable tube 255-1, 255-2 can be connected thereto. For example, the sampling device can be set in an outer frame held by one of the tube clamps 500. As previously described, the sampling device 400 allows sampling and clearing through any cell consumable tube 255-1, 255-2.

[0132] A method of connecting two tubes using the tube connection portion 300 will now be described. In this example, the first cell consumable tube 255-1 is connected to the first cartridge consumable tube 155-1, although it will be appreciated that this method can also be used to connect other tubes 155, 255.

[0133] exist Figure 5A In the figure, the robotic device 5 engages the first box consumable tube 155-1 with a pair of grippers of the end effector, releases it from the passive clamp in the corresponding box 100-1, pulls the tube 155-1 through the top edge 300a of the tube connecting portion 300, and clamps it into the first pair of box consumable tube clamps 500a-1, 500a-1'.

[0134] exist Figure 5B In the figure, the robot device 5 uses a pair of grippers of the end effector to clamp the first cell consumable tube 255-1, send it away from the passive clamp adjacent to the cell consumable 250, pull the tube 255-1 through the bottom edge 300b of the tube connecting part 300, and clamp it into the first pair of cell consumable tube clamps 500b-1, 500b-1' in the second group of tube clamps 500b.

[0135] As combined with the following Fig. 8A and Figure 8B As described, the tube clamp 500 is an active tube clamp 500 for engaging and holding the tube 155 - 1 .

[0136] exist Figure 5C In step (1), the robotic device 5 engages the first box consumable tube 155-1 (e.g., with the first pair of jaws of the end effector) and pulls it through the first pair of box consumable tube clamps 500a-1, 500a-1'. At step (2), the robotic device 5 continues to pull the tube 155-1 through the lower cell consumable tube clamp 500b-1' of the first pair of cell consumable tube clamps 500b-1, 500b-1'. ​​At step (3), the robotic device 5 engages the first cell consumable tube 255-2 below the lower cell consumable tube clamp 500b-1' (e.g., with the second pair of jaws of the end effector while still holding the first box consumable tube 155-1 with the first pair of jaws of the end effector). Since the two tubes 155-1 and 255-1 are respectively held by a corresponding pair of jaws of the end effector, one or more tube clamps (such as the lower cell consumable tube clamp 500b-1') can be opened so that the robotic device 5 pulls the tubes 155-1 and 255-1 away from the surface of the tube connecting part 300.

[0137] Subsequently, the robotic device 5 can perform tube welding between the first box consumable tube 155-1 and the first cell consumable tube 255-1, thereby forming a single connecting tube 355-1 between the first box consumable 150-1 and the cell consumable 250. After welding is completed, at step (4), the robotic device 5 can move the connecting tube 355-1 back to the tube connecting portion 300 so that the connecting tube 355-1 is reengaged by one or more tube clamps (i.e., the tube clamps previously released before welding). At this time, the first pair of jaws and the second pair of jaws of the end effector can be opened to release the connecting tube 355-1. Preferably, the end effector can pull the connecting tube 355-1 upward to eliminate any slack between the first pair of cell consumable tube clamps 500b-1, 500b-1'. In this way, the connecting tube 355 - 1 can be coupled between the first pair of cell consumable tube clamps 500 b - 1 , 500 b - 1 ′ via a peristaltic pump (on the end effector) to pump fluid between the first box consumable 150 - 1 and the cell consumable 250 .

[0138] Now combine Figure 5D Describe the formation of the subsequent connection. At step (1), the tube sealer of the robotic device 5 seals the connecting tube 355-1 between the first pair of box consumable tube clamps 500a-1, 500a-1' (preferably at the top of the gap between the two). Therefore, the connecting tube 355-1 is divided into the first box consumable tube 155-1 and the first cell consumable tube 255-1. At step (2), the robotic device 5 engages the second box consumable tube 155-2 (for example, with the first pair of jaws of the end effector) and pulls it through the second pair of box consumable tube clamps 500a-1, 500a-2'. At step (3), the robotic device 5 continues to pull the tube 155-2 through the lower box consumable tube clamp 500a-2' so that there is enough tubing below the tube clamp 500a-2' for the second box consumable tube 155-2 to reach the first cell consumable tube 255-1 held in the first pair of box consumable tube clamps 500a-1, 500a-1'. At step (4), the robotic device 5 engages the first cell consumable tube 255-1 (e.g., with the second pair of jaws of the end effector while still holding the second box consumable tube 155-2 with the first pair of jaws of the end effector). Since the two tubes 155-2 and 255-1 are respectively held by the corresponding pair of jaws of the end effector, one or more tube clamps (e.g., the lower first box consumable tube clamp 500a-1') can be opened so that the robotic device 5 pulls the tubes 155-2 and 255-1 away from the surface of the tube connecting portion 300.

[0139] At step (5), the robotic device 5 may pull the tubes 155-2 and 255-1 downward so that they are both held below the lower first box consumable tube clamp 500a-1'. Subsequently, the robotic device 5 may perform tube welding between the second box consumable tube 155-2 and the first cell consumable tube 255-1, thereby forming a single connecting tube 355-2 between the second box consumable 150-2 and the cell consumable 250. The robotic device 5 may move the connecting tube 255-2 back to the tube connecting portion 300 so that the connecting tube 355-2 is reengaged by one or more tube clamps (i.e., the tube clamps previously released before welding). At this point, the first pair of jaws and the second pair of jaws of the end effector may be opened to release the connecting tube 355-2. As previously described, the robotic device 5 may further manipulate the tube to eliminate excess slack.

[0140] Although the above steps describe initially connecting the first box consumable tube 155-1 to the first cell consumable tube 255-1 and then connecting the second box consumable tube 155-2 to the first cell consumable tube 255-1, it will be understood that the same steps are also applicable to the connection between any other tubes 155, 255 connected to any consumable 150, 250.

[0141] Alternative fluid connection systems

[0142] although Figure 4A and Figure 4B The fluid connection system 30 shown in FIG. 1 is preferred, but will be combined with FIG. 6A to FIG. 6D A number of alternative fluid connection systems are described. Unless otherwise noted, these alternative systems may share many components with the preferred system already described, and therefore corresponding features are preferably identified using corresponding reference numerals to avoid a detailed description of the common features of each alternative system.

[0143] Fig. 6A A first alternative fluid connection system 30-1 (which may be referred to as a "weld-on-line" arrangement) is shown. This system 30-1 is identical to the preferred fluid connection system 30, except that there is no sampling device 400, and instead an air supply device 80 (e.g., a filter) is provided in the same location. The air supply device 80 can also be used to purge the tube in a manner similar to that described previously, but is not configured to collect fluid samples from the cell consumable 250. To collect the sample, the fluid connection system 30-1 also includes a sampling unit 90 corresponding to Figure 3 The sampling unit 90 described in the embodiment of the present invention has a plurality of sample containers 95. Therefore, although there is a device 400 capable of both sampling and purging, the first alternative fluid connection system 30-1 proves that this is not absolutely necessary. The system 30-1 is relatively simple to implement, but it is difficult to purge the area upstream of the welding point, more welding points may be required for both sampling and purging, and the user may also need to install additional consumables.

[0144] Figure 6B A second alternative fluid connection system 30-2 (which may be referred to as an "integrated into consumable" arrangement) is shown. This system 30-2 is identical to the first alternative fluid connection system 30-1, except that an air supply device 80 is not provided (in the same position as the device 400 of the preferred system), but each cartridge consumable 150-1, 150-2, 150-3, 150-4 has a corresponding air supply device 80-1, 80-2, 80-3, 80-4. For example, an air filter or a bag containing air may be pre-welded on (e.g., each) cartridge consumable 150 and provided with a valve. The valve may include a three-way valve or a stopcock for switching between the air supply device 80 and the cell consumable 250. Alternatively, the valve may include two pinch valves or a pinch valve and a straight-through check valve. The valve may be fully integrated into each cartridge consumable 150 and actuated externally (e.g., by a robotic device and / or an external solenoid valve). Alternatively, the function of the valve can be distributed between the cartridge consumable 150 and the bioprocessing system (i.e., the cartridge consumable 150 includes an air supply device 80 (e.g., a filter) and a line between the cartridge consumable 150, which can be mounted on a valve seat of the bioprocessing system, for example, mounted on the bioprocessing apparatus 1). In this way, the fluid can be returned to the cell consumable 250 by activating the valve and pumping air from one of the air supply devices 80 through the connecting pipe, thereby achieving purging. Advantageously, the fluid can be purged from any position in the connecting pipe (not just downstream of the weld point), and no connection or welding is required to form the weld point. This allows the operator to simply "plug and play". Further advantageously, this fluid connection system 30-2 and the corresponding method can completely purge the pipeline with air before performing any subsequent welding. This can reduce the risk of welding failure because "dry" welding can be performed instead of wet welding (wherein there is still fluid remaining in the tube when welding). However, the cartridge consumable 150 is more complex and needs to be adjusted to include a separate air supply device 80 (which increases the cost of each consumable 150). Furthermore, there is a risk of multiple sterile filters failing, so pre-checking of multiple filters may be necessary prior to use.

[0145] Figure 6CA third alternative fluid connection system 30-3 (which may be referred to as a "switching and manifold" arrangement) is shown. In this system 30-3, there is only a single tube connection portion. In order to allow connection from any box consumable 150 to the cell consumable 250, a manifold 81 with a valve is provided so as to switch between the cell consumable tubes 255-1, 255-2. The manifold 81 with a valve can be pre-connected to the cell consumable 250 and can include an air supply device 80, such as an air filter. This allows many-to-many connections to be achieved between the box consumable 150, the cell consumable tube 255 and the sampling unit 90. In addition, the required tube can be kept relatively short. In addition, the system 30-3 can be operated using only a single pump. However, the manifold 81 is a separate consumable that needs to be prepared and adjusted, thereby increasing the cost and complexity of the system 30-3.

[0146] Fig.6D A fourth alternative fluid connection system 30-4 (which may be referred to as a "double switching partition" arrangement) is shown. In this system 30-4, cell consumable tubes 255-1, 255-2 can be welded to a common intermediate tube 85, which is then welded to any box consumable tube 155. This also achieves many-to-many connections and may be operated using only a single pump. However, it requires the presence of the intermediate tube 85, and each connection may require more welding. In order to perform purging, an air supply 80 can be connected to the intermediate tube 85. Even if other connections are required at the end of the intermediate tube 85, the air supply 80 can still remain in the original position of the intermediate tube 85. The air supply 80 may have a valve that can pump air upward to the box consumable 150 or downward to the cell consumable 250; in this way, multi-directional purging can be performed before sealing. Advantageously, this system 30-4 is relatively simple to implement and can achieve multi-directional purging. However, the switching on the air supply 80 may be complicated, and the air supply is an additional consumable that needs to be installed by the user.

[0147] Sampling device

[0148] A process often performed in a bioprocessing system is sampling, wherein a small amount of fluid is extracted from a cell consumable 250 for testing, for example, monitoring cell growth. The volume range of the sample can be from about 100 μl until up to about 5 ml. In order to test, the sample may need to be transported to a separate cell counter, for example, an "at-line" device. A method of achieving this is to weld the sampling consumable to the first tube 255-1 or the second tube 255-2 of the cell consumable 250. Subsequently, the fluid is pumped from the cell consumable 250 into the sampling consumable, and the connection of the sampling consumable is disconnected to facilitate testing (for example, elsewhere in the bioprocessing system). However, since the tubes 255-1 and 255-2 connected between the cell consumable 250 and the sampling consumable may be very long, a large amount of fluid may remain in the tubes 255-1 and 255-2. The internal fluid path in the rigid manifold is longer, and similar problems may also occur; it should be understood that any feature of the flexible tube described herein may also be applicable to the path inside the rigid fluid manifold. Especially if it is necessary to regularly extract small samples (e.g., about 100 μl) from the cell consumable 250, this may result in a large amount of fluid being wasted in the "dead volume". In addition, if the fluid is left in the tubes 255-1, 255-2 for a long time, the fluid may become invalid. If the invalid fluid is subsequently mixed with other fluids in the bioprocessing system, it may contaminate the remaining fluid.

[0149] Fig. 7A A schematic diagram of a sampling device 400 that solves the above problems is shown. The sampling device 400 has a fluid connection portion 410, which is configured to be connected to a flexible tube 255 containing a fluid consumable (e.g., a cell consumable 250). Although in this example, the cell consumable 250 is a bioreactor 250, it should be understood that the sampling device 400 can be used to sample from any cell-containing consumable in a bioprocessing system. The fluid connection portion 410 may include a fluid connection tube 412, which may be connected to other tubes in the bioprocessing system by tube welding, for example, tubes 255-1, 255-2 connected to the cell consumable 250. The sampling device 400 also includes an air input portion 420, which is configured to allow sterile air to be provided to the device 400. The air input portion 420 may be an air filter that filters air entering the device 400 from the surrounding environment; alternatively, the air input portion 420 may be a syringe or bag containing sterile air.

[0150] The fluid connection tube 412 leads to a first connector 413, which connects the fluid connection tube 412 to the sampling portion 430 and the bypass portion 440. The first connector 413 divides one input into two outputs (or vice versa), and thus may be provided by a Y-connector, a T-connector, or the like.

[0151] The sampling portion 430 may include a sampling tube 432. The sampling tube 432 may have a first end 432a and a second end 432b, wherein the first end 432a of the sampling tube 432 is connected to the fluid connection portion 410 (e.g., via a connector 413). Preferably, the sampling portion 430 is connected to a sample container 434. In this way, when the fluid is pumped into the fluid connection portion 410, the fluid fills the sample container 434. The sample container 434 may have a conical shape, wherein the fluid first fills the narrow end of the cone and then fills toward the wide end of the cone; in this way, when the fluid initially fills the narrow end of the cone, a small volume of fluid can be accurately measured while still allowing the sample container 434 to receive a larger fluid sample. That is, the sample container 434 provides proportional accuracy for small and larger samples of fluid. Alternatively, the length of the sampling tube 432 itself is sufficient to hold the fluid sample. The sampling device 400 may include a level sensor to determine the volume of fluid collected in the sampling portion 430.

[0152] In this example, the second end 432b of the sampling tube 432 is connected to the air supply portion 420. In this way, when the fluid sample fills the sampling portion 430, the air exhausted from the sampling portion 430 can leave the device 400 via the air input portion 420. Alternatively, the sample container 434 can include a bag or a syringe that can expand and contract to accommodate the fluid pumped therein, thereby eliminating the need to connect the sampling portion 430 to the air input portion 420 (e.g., via the second end 432b of the sampling tube 432).

[0153] The bypass portion 440 includes a bypass pipe 442. The bypass pipe 442 may have a first end 442a and a second end 442b. The first end 442a of the bypass pipe 442 is connected to the fluid connection portion 410 (e.g., via the connector 413), and the second end 442b of the bypass pipe 442 is connected to the air input portion 420. When both the sampling pipe 432 and the bypass pipe 442 are connected to the (same) air input portion 420, a second connector 423 may be present. For example, the air input portion 420 may include an air input pipe 422, which is connected to the second end 432b of the sampling pipe 432 and the second end 442b of the bypass pipe 442b via the second connector 423. The second connector 423 divides one input into two outputs (or vice versa), and may therefore be provided by a Y-type connector or a T-type connector. Alternatively, the sampling portion 430 may not be connected to the air input portion 420, or the sampling portion 430 and the bypass portion 440 may be connected to a separate air input portion 420 (eg, a separate air filter or a separate sterile air bag).

[0154] The sampling device 400 also includes a means for restricting fluid flow through the device 400 , such that fluid pumped into the fluid connection portion 410 enters only the sampling portion 430 , and air pumped out of the fluid connection portion 410 passes only through the bypass portion 440 .

[0155] A method for collecting samples can be carried out as follows. First, the fluid connection part 410 is connected to the flexible tube 255-1, 255-2 connected to the fluid-containing consumable (e.g., cell consumable 250). Preferably, the connection is welded by a robot device. Subsequently, the fluid is pumped into the sampling part 430 of the device 400 from the consumable 250 via the fluid connection part 410. Pumping can be achieved using a peristaltic pump that engages the flexible tube 255-1, 255-2 (e.g., downstream of the sampling device 400). The device for limiting the flow of fluid ensures that the fluid entering the device 400 is diverted to the sampling part 430, rather than entering the bypass 442. Once enough fluid is received in the sampling part 430 (e.g., sample container 434), the pumping direction will be reversed. The fluid sample will not be removed from the sample container 434, and the fluid restriction device ensures that air is pumped out of the device 400 from the air input part 420 through the bypass part 440. In other words, when the remaining fluid in the flexible tubes 255-1, 255-2 is pumped back into the cell consumable 250, air is drawn from the air input portion 420 into the flexible tubes 255-1, 255-2 via the bypass tube 442. This means that all the fluid remaining in the flexible tubes 255-1, 255-2 can be returned to the cell consumable 250 while still retaining the fluid sample in the device 400.

[0156] Means for limiting the flow of fluid through the device 400 can be provided by a first check valve 435 to allow fluid to flow only from the fluid connection portion 410 into the sampling portion 430. More specifically, the first check valve 435 is disposed along the sampling tube 432 and limits the movement of fluid only from the first end 432a of the sampling tube 432 to the second end 432b of the sampling tube 432. The first check valve 435 only allows fluid to flow in one direction, meaning that air from the air supply portion 420 will not clear the fluid sample in the sampling portion 430. The first check valve 435 is preferably located on the sampling tube 432 between the sample container 434 and the air input portion 420; thus, the fluid sample does not need to pass through the first check valve 435.

[0157] Means for limiting the flow of fluid through the device 400 can be provided by a second check valve 445 to allow fluid to flow only from the air supply input portion 420 through the bypass tube 442 to the fluid connection portion 410. More specifically, the second check valve 445 is disposed along the bypass tube 442 and limits the movement of fluid (e.g., air) only from the second end 442b of the bypass tube 442 to the first end 442a of the bypass tube 442. The second check valve 445 only allows fluid to flow in one direction, meaning that fluid from the fluid connection portion 410 does not enter the bypass tube 442.

[0158] As an alternative to using either or both of the check valves 435, 445, the means for restricting fluid flow may be provided by a portion of a clampable tubing. For example, the sampling tube 432 and / or the bypass tube 442 may be made of flexible tubing that may be clamped by an external pinch valve during use. During pumping of fluid into the device 400, the bypass tube 442 may be clamped so that the fluid is diverted to the sampling tube 432; during pumping of fluid out of the device 400, the sampling tube 432 may be clamped so that air is diverted from the air input portion 420 to the fluid connection portion 410 via the bypass tube 442.

[0159] The sampling portion 430 may include an extraction port ( Fig. 7A 430 ) for removing a fluid sample from the sampling portion 430. For example, once the fluid is collected in the sample container 434, a syringe can be connected to the extraction port and the fluid sample can be removed from the extraction port. The extraction port can include a needleless connector for use with a syringe needle, a Luer lock cap port, or a septum.

[0160] The device 400 may include an outer housing (not shown). The outer housing may include a frame for holding components of the device 400 in predetermined positions relative to each other; holding components of the device 400 (such as the fluid connection portion 410, the air input portion 420, and the extraction port) in predetermined positions helps the robotic device perform consistent engagement. The outer housing may have one or more engagement features to facilitate installation of the device 400 within a bioprocessing system (e.g., so as to be retained in a tube clamp), or to facilitate manipulation of the device 400 by a robotic device. Alternatively or in addition, multiple sampling devices may be retained in a single box (e.g., a sampling box) so that a user can easily load them into a bioprocessing system and then move them within the bioprocessing system by the robotic device 5. For example, the sampling box may include a housing configured to hold one or more devices 400 (e.g., ten devices 400), which can be used one by one as needed in a bioprocessing system.

[0161] It should be understood that any of the components described above (eg, sampling tube 432) may be provided by multiple components connected together. Figure 7BAn exploded view of the device 400 is shown, wherein the various parts are provided by the components shown in Table 1:

[0162] Table 1

[0163] serial number describe 470 Press-in plug 471 Flexible tube: 1 / 8 inch inner diameter, 1 / 4 inch outer diameter 472 Straight through buckle connector 473、477、479、481 PVC pipe: inner diameter 1 / 8 inch, outer diameter 3 / 16 inch 474、476、480 Female Luer Lock Sidearm Y-Connector 475 Soft PVC welding pillow with a volume of 4ml 477 Men's Luer Cap 478 Check valve 482 Female Luer Lock Inverted Connector 483 Transducer protector with female Luer lock inlet and male Luer lock outlet 484 Male Luer Lock 485 PVC pipe: inner diameter 0.118 inches, outer diameter 0.161 inches 486 Check valve

[0164] The soft PVC welding pillow 465 can be glued to the Y-joints 474, 476 using, for example, a cyanoacrylate adhesive.

[0165] Figure 7B The arrangement of components shown in is only an example, and the shape of the device 400 can be adjusted. For example, Figure 7C An alternative arrangement of the device 400 is shown, in which the fluid connection portion 410 and the air input portion 420 are arranged adjacent to each other.

[0166] Pipe clamp

[0167] Next, we will combine Fig. 8A and Figure 8B An example of a pipe clamp 500 is described. Fig. 8A The assembled pipe clamp 500 is shown. Figure 8B An exploded view of the pipe clamp 500 is shown to allow viewing of its internal components. As shown, the components are generally assembled using a plurality of screws 590, although not all screws 590 are labeled for clarity.

[0168] The tube clamp 500 includes a body 510 that facilitates connecting the tube clamp 500 to other parts of a bioprocessing system, such as the tube connection portion 300 described above.

[0169] The tube clamp 500 has a tube seat 520, and the profile of the tube seat 520 is designed to receive the tube at a predetermined position of the tube seat 520. In this example, the profile is generally "C" shaped. Alternatively, the profile can also be "V" shaped, rectangular, semicircular, or any other shape suitable for holding and receiving the tube at a predetermined position. The tube seat 520 is connected to the top surface 510a of the body 510 by, for example, one or more screws.

[0170] The tube clamp 500 further includes a retaining element 530 including a retaining arm 531. By moving the retaining element 530, the retaining arm 531 can be moved relative to the tube seat 520 between an open position for allowing the tube to be received by the tube seat 520 and a closed position for retaining the tube in a predetermined position of the tube seat 520. The retaining arm 531 may have a step (or a stepped portion) so that the same tube clamp 500 can be used for tubes of different diameters. The retaining arm 531 may be hook-shaped.

[0171] Preferably, the tube seat 520 includes a first (upper) portion 522 and a second (lower) portion 524, wherein the upper portion 522 and the lower portion 524 of the tube seat 520 are spaced apart parallel to the axis of the tube to provide a gap, and the retaining arm 531 is arranged to contact the tube within the gap. In this way, the retaining arm 531 can apply a symmetrical force to the tube so that it will not bend during the joining process.

[0172] The tube clamp 500 also includes an actuator 540 configured to move the retaining arm 531 between an open position and a closed position. The actuator 540 is controllable to move the retaining arm 531 between a plurality of intermediate positions. This allows the tube clamp 500 to properly engage (and / or clamp) tubes of different diameters, for example, a 4 mm tube or a 6 mm tube. In addition, at each intermediate position, the retaining arm 531 can apply a different force to the tube against the tube seat 520, thereby controlling the flow of fluid through the tube. For example, the closed position can apply a force sufficient to clamp the tube closed (i.e., block the tube) to prevent fluid from flowing through. One intermediate position can hold the tube tightly to limit (but not prevent) fluid from flowing through. Another intermediate position can hold the tube loosely without significantly restricting fluid from flowing through. Preferably, the actuator 540 can move the retaining arm 531 through a continuous range of positions to apply a continuous range of forces to the retained tube.

[0173] The actuator 540 is housed inside the body 510. The actuator 540 is connected to the retaining element 530 via a shaft 542 extending from the top surface 510a of the body 510. The actuator 540 is preferably a motor that provides rotational movement of the shaft 542, thereby rotating the retaining arm 531 to move between the open and closed positions. The retaining element 530 can be biased by a spring 534 to offset the force applied by the actuator 540; thus, when the actuator 540 is disconnected, the retaining arm 531 automatically moves to the closed position. More specifically, the spring 534 pulls the retaining arm 531 to the closed position to engage (but not clamp) the tube. This provides a failsafe to prevent the tube from falling off, and allows the actuator 540 to be controllable in only one direction of rotation.

[0174] In addition to the rotational movement of the retaining element 530, the force from the actuator 540 is transmitted to the retaining element 530 through the cam element 528 (herein referred to as the "clamping cam"), so that the retaining arm 531 also moves laterally when moving between the open position and the closed position. The clamping cam 528 is mounted in the opening 525 of the tube seat 520. A first bearing 526 is provided in the opening 525 to facilitate smooth movement of the clamping cam 528 relative to the tube seat 520. The clamping cam 528 has a lobed portion, so that during the continued rotation of the retaining element 530 (for example, to bring the retaining arm 531 in front of the tube seat 520), the retaining arm 531 subsequently moves laterally toward the tube seat 520 to compress the tube between the retaining arm 531 and the tube seat 520. The spring 534 also regulates this lateral movement.

[0175] A cap 544 may be provided to connect the retaining element 530 and the socket 520 to the body 510 via the shaft 542. To facilitate smooth movement of the retaining element 530 relative to the cap 544, an opening 536 is provided in the retaining element 530, in which a second bearing 536 may be provided.

[0176] The cam 528 is mounted directly on the actuator 540 and supported by the first bearing 526. The upper portion of the cam 528 fits into the second bearing 536, which is offset from the center of rotation of the actuator 540. Due to this offset, the retaining element 530 moves laterally during the rotation of the cam 528. On the opposite side of the raised portion of the cam 528, there is an arm drive having a vertically protruding lug that engages with the retaining element 530; thus, the rotation of the cam 528 also rotates the retaining element 530 and the retaining arm 531.

[0177] The tube clamp 500 may also include a tube guide 550. The tube guide 550 may include a second tube seat 551 that is longitudinally offset (offset along the axis of the received tube) relative to the first tube seat 520. The tube guide 550 may also include a front fin 552 that is arranged to extend closely along the longitudinal axis of the tube. In this way, the tube guide 550 helps to hold the tube along a predetermined axis, thereby improving the consistency of the external robotic device in engaging the held tube. Because the front fin 552 is thinner than the spacing of the jaws when the robotic device clamps the tube, the front fin 552 can continue to support the tube during the engagement process. The tube guide 550 can be connected to the front surface 510b of the body 510 of the tube clamp 500 by one or more screws 590 (only partially labeled).

[0178] The tube clamp 500 may also include at least one sensor for detecting one or more of the following: the presence of a portion of the tube in the tube clamp 500 and / or whether a portion of the tube held in the tube clamp 500 contains a fluid. For example, the at least one sensor may be a bubble sensor 560 disposed on the front surface 510b of the body 510 of the tube clamp such that the longitudinal axis of the held tube passes through the bubble sensor 560. The bubble sensor 560 is configured to detect whether the tube is wet or dry.

[0179] The at least one sensor may also include a force sensor (not shown) for sensing the force (e.g., torque) applied by the retaining arm to the tube, thereby indicating whether a tube is present in the tube clamp 500. The combination of the bubble sensor 560 and the force sensor allows the tube clamp 500 to determine whether a tube is present, and whether the tube is wet or dry. The force sensor may be connected to the actuator 540 in a control loop, thereby allowing a precise force to be applied to the tube. This is particularly advantageous when using different sized tubes in the tube clamp 500, as the actuator 540 can clamp to a predetermined consistent force (regardless of the tube size), thereby achieving consistent engagement.

[0180] The pipe clamp 500 may include a processor 580 housed within the body 510. The processor 580 may receive external instructions, such as instructions to operate the actuator 540 to move the retaining arm 531 between an open position, a closed position, and a plurality of intermediate positions. The processor 580 may receive measurements from at least one pipe sensor. These measurements may be recorded and / or transmitted externally by the processor. As described above, a force sensor may be connected to the actuator 540 in a control (feedback) loop to apply a precise force to the pipe.

[0181] Alternative sampling and purging devices

[0182] Several alternative sampling / scavenging devices and methods are briefly described below.

[0183] Fig.9A The first way to extract a sample from a cell consumable is shown, referred to as the "upstream" option. Here, an air source is built into the tubing and can be used to generate "slugs" of fluid in the tube. The tube can then be sealed and the sample removed. The steps are as follows: (1) mechanically mount and weld to the cell consumable; (2) mount and weld the sampling device on the tube (or additional length of tubing); (3) pump the fluid until a sufficient volume of fluid has been sampled through the valve, then activate the valve and continue pumping, pumping air into the tubing and "slugs" into the sampling device; (4) seal the sample; (5) repeat steps (2)-(4) to generate subsequent samples. This process is deterministic, maintains a relatively short length of tubing, allows for the collection of variable volumes of sample (slug length depends on the amount pumped), and provides flexibility in the choice of output container.

[0184] Fig. 9B A second way of extracting samples from cell consumables is shown, referred to as the “post hoc” option. Here, after sampling, the air source is repeatedly welded on a new sample line. The steps are as follows: (1) weld the sample with a filter; (2) pump the sample to a certain level; (3) weld out the sample segment and replace it with a new segment; (4) allow the air to fall back and purge the line. The process is simple overall. However, due to the constant changes in the welded line, sampling may become difficult when a large number of samples need to be collected. In addition, it is difficult to keep the line length short and to accurately control the sample volume. Similarly, in order to provide flexibility in the output sample container, the weld needs to be predetermined (welded on both sides).

[0185] Fig. 9C A third way of extracting a sample from a cell consumable is shown, referred to as the "built-in consumable" option. The steps proceed as follows: (1) weld the sample; (2) optionally, clear the tube; (3) pump into the sample container; (4) seal. This is relatively simple, with the only limitation being that the sample container needs to be welded in advance. This option is deterministic, although sample extraction may be difficult. This option keeps the tube relatively short and allows for extraction of variable volumes of sample (although it may be difficult for smaller samples). Flexibility in the output sample container may also be difficult, as the presence of air provides an "air spring" that impedes fluid flow.

[0186] Fig.9D A fourth way of extracting samples from cell consumables is shown, called the "top air line with expandable volume" option. Here, a continuous tube leading to an air supply (air filter or expandable volume) is provided, and branch lines provide a sealable, expandable volume (e.g., a bag or syringe). The steps are as follows: (1) install and weld the sampling equipment; (2) open the branch line to be sampled; (3) pump into the selected branch line (preferably, if the tube leading to the air supply is blocked); (4) seal the selected branch line and remove. Although this option is not particularly simple, it is deterministic, keeps the tube length appropriately short, allows variable volume of fluid sample, and allows flexibility of output container.

[0187] Fig.9E A fifth way of extracting samples from a cell consumable is shown, called the "Pinch Valve Manifold" option, which is a variation of the "Top Gas Line with Expandable Volume" option. Here, pinch valves are placed on the branch lines.

[0188] Fig.9FA sixth way of extracting a sample from a cell consumable is shown, called the "sampling line draw down" option, which is a variation of the "after the fact" option. Here, a section of tubing is preloaded onto a reel with a filter. Since the tube can be very long, a large number of samples can be collected using the reel. The steps are as follows: (1) connect the end of the tube to the cell consumable; (2) pump a certain volume of fluid from the cell consumable into the tube; (3) seal either side of the tube with a certain volume of fluid and remove the sealed portion of the tube; (4) pump the remaining fluid out of the (new) end of the tube.

[0189] Figure 9G Another variation of the "sample line aspiration" option is shown. Here, a string of wider inner diameter consumables can be provided (e.g., 5 mm inner diameter to provide 5 cm long sample per 1 ml). The string of consumables can have evenly spaced pre-set ports or built-in check valves and connectors. Fig.9F Although it provides more structure than the options above, it increases the complexity of manufacturing.

[0190] Although the foregoing is directed to exemplary embodiments of the present invention, it should be understood that the present invention is described herein only by way of example and that modifications may be made to the details within the scope of the invention. Furthermore, it will be understood by those skilled in the art that the present invention is not limited to the embodiments disclosed herein, nor to any details not described in detail in the drawings or defined in the claims. In fact, redundant features in the drawings may be removed without adversely affecting the present invention.

[0191] Moreover, other and further embodiments of the present invention will become apparent to those skilled in the art from consideration of this specification and may be devised without departing from the basic scope of the invention, which is determined by the appended claims.

Claims

1. A device for collecting a fluid sample from a fluid-containing consumable in a bioprocessing system, the consumable having a tube fluidically connected thereto, the device comprising: a fluid connection portion configured to connect to a tube containing a fluid consumable and to pump fluid or air through the device; as well as an air input portion configured to allow sterile air to be supplied to the device; a sampling portion connected to the fluid connection portion, wherein the sampling portion is configured to receive a fluid sample from the consumable via the fluid connection portion during pumping into the device; a bypass tube having a first end connected to the fluid connection portion and a second end connected to the air input portion, wherein the bypass tube is configured to receive air provided from the air input portion and direct the air out of the device via the fluid connection portion without passing through the sampling portion, thereby clearing fluid in a tube connected to the consumable; and Means for restricting fluid flow through each of the sampling portion and the bypass conduit allow fluid pumped into the fluid connection portion to enter only the sampling portion and air pumped out of the fluid connection portion to pass only through the bypass conduit.

2. The apparatus according to claim 1, further comprising: A sampling tube has a first end connected to the fluid connection portion and a second end connected to the air input portion, wherein the sampling portion is disposed between the first end and the second end of the sampling tube.

3. The device according to claim 2, wherein: The sampling portion is provided by a sample container disposed between the first end and the second end of the sampling tube.

4. The device according to claim 3, wherein: The sample container has a conical shape.

5. A device according to any preceding claim, wherein: The sampling portion includes an extraction port for removing the fluid sample from the sampling portion.

6. A device according to any preceding claim, wherein: The means for restricting fluid flow through the device comprises a check valve to allow fluid to flow from the fluid connection portion into the sampling portion.

7. Apparatus according to claim 6, when dependent on claim 2, wherein: The check valve is located on the sampling pipe between the sampling part and the air input part.

8. A device according to any preceding claim, wherein: The means for restricting fluid flow through the device includes a check valve to allow air to flow from the air input portion through the bypass conduit to the fluid connection portion.

9. A device according to any preceding claim, wherein: The fluid connection portion comprises a length of flexible tubing, thereby enabling the device to be connected to the tubing of the consumable by tube welding.

10. A device according to any preceding claim, wherein: The air input portion is an air filter configured to provide sterile air from a surrounding environment.

11. The device according to any one of claims 1 to 9, wherein: The air input part includes a sterile air container.

12. An apparatus according to any preceding claim, wherein: The air input portion is a single air input portion connected to both the sampling portion and the bypass pipe.

13. A device according to any preceding claim, further comprising an outer housing.

14. A sampling cartridge comprising a housing configured to hold one or more devices according to any preceding claim.

15. A method of collecting a fluid sample using the device of any preceding claim, comprising: Connecting the fluid connection portion to the tube connected to the consumable; pumping fluid from the consumable into a sampling portion of the device via the fluid connection portion; as well as The remaining fluid in the tube is pumped back to the consumable, thereby drawing air from the air input portion into the tube via the bypass tube.

16. A consumable for a biological treatment system, the consumable comprising: Containers for fluids, A tube connected at a first end to the container and extending to a second end, and An air supply is fluidly connected to the tube at a location between the first end and the second end.

17. A pipe clamp for holding a partially flexible pipe, comprising: a tube holder configured to receive the tube at a predetermined position; a retaining element movable relative to the tube seat between an open position for allowing the tube to be received by the tube seat at the predetermined position and a closed position for retaining the tube in the tube seat; an actuator configured to move the retaining element between the open position and the closed position; Wherein, the actuator is further configured to move the retaining element beyond the closed position so that the tube is at least partially clamped against the tube seat, thereby enabling control of fluid flow through the tube.

18. The pipe clamp according to claim 17, wherein: The actuator is controllable to provide a continuous range of intermediate positions of the retaining element.

19. The pipe clamp according to claim 17 or 18, wherein: The tube clamp is configured to enable the tube to move longitudinally therethrough.

20. The pipe clamp according to any one of claims 17 to 19, wherein: The retaining element comprises a retaining arm arranged to enclose the tube within the tube seat when the retaining element is in the closed position, and wherein the tube seat comprises a first portion and a second portion spaced apart by a gap in a direction parallel to an axis of the tube, the retaining arm being arranged to contact the tube within the gap.

21. The pipe clamp according to any one of claims 17 to 20, further comprising: At least one sensor for detecting one or more of: the presence of a portion of tubing in the tubing clamp and / or whether the portion of tubing held in the tubing clamp contains a fluid.

22. The pipe clamp according to any one of claims 17 to 21, further comprising: A tube guide is arranged to support the tube at a predetermined position along an axis of the tube offset from the tube seat.

23. A fluid connection system for a bioprocessing device, comprising: a consumable storage portion having a first sub-portion and a second sub-portion, each sub-portion configured to store at least one fluid-containing consumable having a flexible tube fluidly connected thereto; a cell storage portion configured to store a cell-containing consumable having a first flexible tube and a second flexible tube, each tube being fluidly connected to the cell-containing consumable; A tube connection part is arranged between the consumable storage part and the cell storage part, and the tube connection part includes: a first portion configured to hold a first flexible tube of the cell-containing consumable and position it to connect to a flexible tube corresponding to a fluid-containing consumable stored in a first subsection of the consumable storage portion; A second portion is configured to hold a second flexible tube of the cell-containing consumable and is positioned to connect to a flexible tube corresponding to a fluid-containing consumable stored in a second subsection of the consumable storage portion.

24. The fluid connection system of claim 23, wherein: The tube connection portion is further arranged to arrange the first flexible tube and the second flexible tube containing the cell consumable to be connected to an air supply device.

25. The fluid connection system according to claim 23 or 24, wherein: The tube connection portion is further arranged to connect the first flexible tube and / or the second flexible tube containing the cell consumable to a sample collection device.

26. The fluid connection system of claim 24, wherein: The tube connecting portion is also arranged to arrange the first flexible tube and / or the second flexible tube containing the cell consumable to be connected to the sample collection device, and wherein the tube connecting portion is configured to arrange the first flexible tube and / or the second flexible tube containing the cell consumable to a single device, which provides the air supply device and the sample collection device.

27. A fluid connection system according to any one of claims 23 to 26, wherein: The consumable storage portion includes a plurality of consumable holding locations, preferably arranged in a linear configuration.

28. The fluid connection system of claim 27, wherein: The pipe connecting part comprises: a first set of tube clips, wherein each consumable holding position in the first subsection corresponds to at least one tube clip in the first set of tube clips; and A second set of tube clamps, wherein each flexible tube connected to the cell-containing consumable corresponds to at least one tube clamp in the second set of tube clamps.

29. The fluid connection system of claim 28, wherein: The at least one pipe clamp comprises: a tube holder configured to receive the tube at a predetermined position; a retaining element movable relative to the tube seat between an open position for allowing the tube to be received by the tube seat in the predetermined position and a closed position for retaining the tube in the tube seat; and an actuator configured to move the retaining element between the open position and the closed position; Wherein, the actuator is further configured to move the retaining element beyond the closed position so that the tube is at least partially clamped against the tube seat, thereby enabling control of fluid flow through the tube.

30. The fluid connection system according to claim 28 or 29, wherein: The at least one tube clamp comprises at least one sensor for detecting one or more of: the presence of a portion of a tube in the tube clamp and / or whether the portion of a tube held in the tube clamp contains a fluid.

31. A bioprocessing apparatus comprising a fluid connection system according to any one of claims 23 to 30.

32. The bioprocessing apparatus of claim 31, further comprising one or more of a loading system, a storage system, a cultivation system, and an unloading system.

33. A biological treatment system comprising: A fluid connection system according to any one of claims 23 to 30 and / or a bioprocessing device according to claim 31 or 32.

34. The bioprocessing system of claim 33, further comprising: A robotic device is configured to manipulate a fluid connection between one or more flexible tubes of the bioprocessing system.

35. A method of connecting a first flexible tube connected to a first consumable material with a second flexible tube connected to a second consumable material using a robotic device, comprising: engaging the first flexible tube retained in a first tube clamp and pulling the first flexible tube through the first tube clamp to position the first flexible tube adjacent to the second flexible tube retained in a second tube clamp; engaging the second flexible tube while maintaining engagement of the first flexible tube with the robotic device; as well as The first flexible tube is welded to the second flexible tube to form a connecting tube connecting the first consumable to the second consumable.

36. The method of claim 35, further comprising: The second pipe is removed from the second pipe clamp before welding, and the connecting pipe is returned to the second pipe clamp after welding.

37. The method according to claim 35 or 36, further comprising: Sealing the connecting tube between the first tube clamp and the second tube clamp to separate the connecting tube into a first flexible tube held in the first tube clamp and a second flexible tube held in the second tube clamp; engaging a third flexible tube held in a third tube clamp, the third flexible tube being connected to a third consumable, and pulling the third flexible tube through the third tube clamp to position the third flexible tube adjacent to the first flexible tube or the second flexible tube; engaging the first flexible tube or the second flexible tube while maintaining the third flexible tube engaged with the robotic device; as well as The third flexible tube is welded to the first flexible tube or the second flexible tube to form a second connecting tube connecting the first consumable or the second consumable to the third consumable.

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